chr19-13261526-C-T

Position:

• chr19-13261526-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001127222.2(CACNA1A):​c.4174G>A​(p.Val1392Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21 O:1
• Conservation: PhyloP100: 7.88

Genes affected

CACNA1A (HGNC:1388): (calcium voltage-gated channel subunit alpha1 A) Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas, the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1A subunit, which is predominantly expressed in neuronal tissue. Mutations in this gene are associated with 2 neurologic disorders, familial hemiplegic migraine and episodic ataxia 2. This gene also exhibits polymorphic variation due to (CAG)n-repeats. Multiple transcript variants encoding different isoforms have been found for this gene. In one set of transcript variants, the (CAG)n-repeats occur in the 3' UTR, and are not associated with any disease. But in another set of variants, an insertion extends the coding region to include the (CAG)n-repeats which encode a polyglutamine tract. Expansion of the (CAG)n-repeats from the normal 4-18 to 21-33 in the coding region is associated with spinocerebellar ataxia 6. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a repeat III (size 283) in uniprot entity CAC1A_HUMAN there are 14 pathogenic changes around while only 1 benign (93%) in NM_001127222.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1A. . Gene score misZ 5.7845 (greater than the threshold 3.09). Trascript score misZ 3.9354 (greater than threshold 3.09). GenCC has associacion of gene with benign paroxysmal torticollis of infancy, developmental and epileptic encephalopathy, 42, undetermined early-onset epileptic encephalopathy, episodic ataxia type 2, familial or sporadic hemiplegic migraine, spinocerebellar ataxia type 6, Lennox-Gastaut syndrome, migraine, familial hemiplegic, 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928
• PP5: Variant 19-13261526-C-T is Pathogenic according to our data. Variant chr19-13261526-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 195935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13261526-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.4174G>A	p.Val1392Met	missense_variant	26/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4174G>A	p.Val1392Met	missense_variant	26/47	1	NM_001127222.2	ENSP00000353362

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1448688 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 719322

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2022	Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29056246, 27959697, 28007337, 30283815, 31487502, 31468518, 29100083, 34489640, 33258288, 33425808, 34102571) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 31, 2017	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 20, 2019	- -

Developmental and epileptic encephalopathy, 42 Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -
Likely pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Dec 14, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000195935, PS1_S). The variant has been previously reported as de novo in a similarly affected individual (PMID: 28007337, 29100083, PS2_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000280773,VCV001285568, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.889, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 20, 2022	This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_VSTR, PS4, PM5_STR, PS3_MOD, PM2_SUP, PP2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 03, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Episodic ataxia type 2 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Pediatrics, MediClubGeorgia	Apr 25, 2021	This variant has previously been described as disease causing for Ataxia, ClinVar lists this variant as pathogenic (Variation ID: 195935) and uncertain (Variation ID: 195935) and likely pathogenic (ID: 195935). This variant is absent parents. PolyPhen: Probably damaging ; Align-GVGD: C0; MutationTaster: Disease causing Conservation_nt: high; Conservation_aa: weak; This variant is absent in population databases. -

Migraine, familial hemiplegic, 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	May 07, 2019	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3,PP4. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Pathogenic:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 12-31-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2022	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1393 of the CACNA1A protein (p.Val1393Met). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CACNA1A function (PMID: 31468518). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1A protein function. ClinVar contains an entry for this variant (Variation ID: 195935). This variant is also known as NM_023035.2:c.4186G>A (p.V1396M). This missense change has been observed in individual(s) with epileptic encephalopathy and ataxia, tremor, developmental delay, and epilepsy (PMID: 28007337, 29056246, 29100083, 30283815). In at least one individual the variant was observed to be de novo. -

Spinocerebellar ataxia type 6 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Baylor Genetics

Oct 16, 2014

Our laboratory reported dual molecular diagnoses in CACNA1A (NM_001174080.1, c.4177G>A) and SLC26A1 (NM_022042.2, c.1487T>G) in one individual with reported features of intractable epilepsy, global developmental delay, tremor, ataxia, hyperlipidemia, growth hormone deficiency, and stable right optic nerve glioma. Missense and truncating variants in CACNA1A have been reported in patients with epilepsy (PMID:18940563;PMID:21703448) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 04, 2020

The alteration results in an amino acid change:_x000D_ _x000D_ The c.4177G>A (p.V1393M) alteration is located in coding exon 26 of the CACNA1A gene. This alteration results from a G to A substitution at nucleotide position 4177, causing the valine (V) at amino acid position 1393 to be replaced by a methionine (M). The alteration is not observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the CACNA1A c.4177G>A alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals:_x000D_ _x000D_ The c.4177G>A (p.V1393M) alteration has been observed de novo in multiple unrelated affected patients. Common clinical features include seizures, ataxia, tremors, developmental delay, and intellectual disability (Travaglini, 2017; Butler, 2017; Cordeiro, 2018; Costain, 2019; Jiang, 2019). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.V1393 amino acid is conserved in available vertebrate species. The amino acid is located in a functionally important protein domain:_x000D_ _x000D_ The p.V1393 amino acid is located in the S5 transmembrane segment of domain III of the Cav2.1 P/Q type voltage-dependent calcium channel. The S5 and S6 helices line the inner pore surface of the ion channel (Rajakulendran, 2012). Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ _x000D_ Functional analysis using whole cell voltage-clamp recordings of the mouse homologous variant in HEK293 cells demonstrated that the p.V1393M alteration increased peak density compared to wild type and altered current kinetics with a steeper activation curve and midpoint of activation that was more hyperpolarized. In addition, expression levels of mutant protein in the cell membrane was 50% of wild type expression levels (Jiang, 2019). The alteration is predicted deleterious by in silico modeling:_x000D_ _x000D_ The p.V1393M alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Migraine Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4479236:Developmental and epileptic encephalopathy, 52 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Wendy Chung Laboratory, Columbia University Medical Center

Mar 20, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	.;.;.;.;H;.;.;.;.;.;.;.;H;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.7	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.79
MutPred		0.73		.;.;Loss of catalytic residue at V1393 (P = 0.0413);Loss of catalytic residue at V1393 (P = 0.0413);Loss of catalytic residue at V1393 (P = 0.0413);.;Loss of catalytic residue at V1393 (P = 0.0413);.;.;Loss of catalytic residue at V1393 (P = 0.0413);Loss of catalytic residue at V1393 (P = 0.0413);.;Loss of catalytic residue at V1393 (P = 0.0413);.;Loss of catalytic residue at V1393 (P = 0.0413);
MVP		0.97
MPC		2.4
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.42
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs794727411; hg19: chr19-13372340;